RECIST Measurements Research Articles

EP.08F.10 Semi-Automated NSCLC Segmentation and RECIST Measurement: Bridging the Gap Between Speed and Radiologist-Level Accuracy

EP.08F.10 Semi-Automated NSCLC Segmentation and RECIST Measurement: Bridging the Gap Between Speed and Radiologist-Level Accuracy

Weakly supervised detection of pheochromocytomas and paragangliomas in CT using noisy data

Pheochromocytomas and Paragangliomas (PPGLs) are rare adrenal and extra-adrenal tumors that have metastatic potential. Management of patients with PPGLs mainly depends on the makeup of their genetic cluster: SDHx, VHL/EPAS1, kinase, and sporadic. CT is the preferred modality for precise localization of PPGLs, such that their metastatic progression can be assessed. However, the variable size, morphology, and appearance of these tumors in different anatomical regions can pose challenges for radiologists. Since radiologists must routinely track changes across patient visits, manual annotation of PPGLs is quite time-consuming and cumbersome to do across all axial slices in a CT volume. As such, PPGLs are only weakly annotated on axial slices by radiologists in the form of RECIST measurements. To ameliorate the manual effort spent by radiologists, we propose a method for the automated detection of PPGLs in CT via a proxy segmentation task. Weak 3D annotations (derived from 2D bounding boxes) were used to train both 2D and 3D nnUNet models to detect PPGLs via segmentation. We evaluated our approaches on an in-house dataset comprised of chest-abdomen-pelvis CTs of 255 patients with confirmed PPGLs. On a test set of 53 CT volumes, our 3D nnUNet model achieved a detection precision of 70% and sensitivity of 64.1%, and outperformed the 2D model that obtained a precision of 52.7% and sensitivity of 27.5% (p< 0.05). SDHx and sporadic genetic clusters achieved the highest precisions of 73.1% and 72.7% respectively. Our state-of-the art findings highlight the promising nature of the challenging task of automated PPGL detection.

A pilot trial of autologous tumor infiltrating lymphocytes (lifileucel, LN-144) for patients with asymptomatic melanoma brain metastases.

TPS9603 Background: Melanoma brain metastases (MBM) are a leading cause of morbidity and mortality for patients with advanced melanoma. Modern systemic therapies are insufficient at controlling MBM, resulting in median overall survival (OS) of &lt;1 year. Adoptive T cell therapy, using tumor infiltrating lymphocytes (TIL), has demonstrated efficacy in treating advanced melanoma. Lifileucel (LN-144), an autologous TIL product, was recently shown to be safe and effective for patients with PD-1 refractory melanoma. However, no trials have yet explored lifileucel in patients with active MBM. Methods: This single-center pilot trial (NCT05640193) aims to enroll 10 pts with asymptomatic MBM from non-uveal melanoma to receive lifileucel. Patients must have ≥1 intracranial lesion measuring 5-30mm visible on MRI to be used as a target lesion for modified (m)RECIST measurement, progression on prior anti-PD-1 therapy (with or without anti-CTLA-4), progression on targeted therapy (if BRAF V600E/K-mutated), ECOG PS ≤1, ≥1 resectable lesion(s) (≥1.5 cm), recovered from prior surgery/anticancer treatment-related AEs (grade ≤1). Patients are ineligible if they have symptomatic MBM and/or require corticosteroids of ≥10 mg/day of prednisone or equivalent. Lifileucel is generated from resected tumor in a centralized GMP process. The regimen includes nonmyeloablative lymphodepletion with cyclophosphamide 750 mg/m2 on days 1-3 and fludarabine 30 mg/kg on days 1-4 (reduced dose compared with standard lifileucel protocol), lifileucel infusion, and up to 6 doses of high-dose IL-2. The primary endpoint is feasibility, defined as ≥7/10 patients who undergo tumor resection successfully receiving lifileucel infusion. Secondary endpoints are safety, feasibility of manufacturing lifileucel in patients with MBM, and brain metastasis response rate (BMRR) per mRECIST 1.1. Exploratory endpoints include overall objective response rate by mRECIST 1.1, best extracranial response rate, intracranial progression-free survival (PFS), overall PFS, OS. Extensive correlative analyses of peripheral blood mononuclear cells, plasma, tumors, and cerebrospinal fluid are planned to better understand MBM growth, treatment resistance, and response of the central nervous system to lifileucel. Clinical trial information: NCT05640193 .

Abstract 2497: Extracellular vesicle based ALPPL2 and THBS2 as biomarkers for disease monitoring in patients with pancreatic ductal adenocarcinoma

Abstract Pancreatic ductal adenocarcinoma (PDAC) remains a formidable challenge in the realm of oncology, characterized by its aggressive nature and resistance to treatment. Several therapeutic regimens have been shown to extend patient survival, but the majority of the patients become refractory to the treatments in a short period of time. Hence, it is critical to monitor a patient’s response to treatment in a timely manner so that different treatment regimens can be considered promptly. Currently, CA19-9 is the most common blood-based marker being used to monitor disease burden in patients with PDAC. However, 15-20% of patients with PDAC do not have elevated blood CA19-9 levels. In this study, we sought to determine the utility of two circulating extracellular vesicle (EV) based protein biomarkers, ALPPL2 (Alkaline phosphatase, placental-like 2) and THBS2 (Thrombospondin 2), for disease monitoring in patients with PDAC. We first established and optimized EV assays using the ExoViewTM platform for detecting and quantifying the number of ALPPL2+ or THBS2+ EVs in serum samples. We then determined the concentrations of ALPPL2+ or THBS2+ EVs in samples from healthy individuals and longitudinal samples from patients with Stage IV PDAC undergone treatment. The longitudinal samples were from 26 patients of which 16 were CA19-9 secretors (defined as &amp;gt;35 U/ml) and 10 were CA19-9 non-secretors (defined as &amp;lt;35 U/ml) that were treated with various regimens for 4-24 months with monthly blood sample collection and CT scans (a total of 305 samples). We found that the concentrations of ALPPL2+ and THBS2+ EVs are on average 1,737 and 1,113 times higher in PDAC patients than in the healthy controls, respectively. Correlation analysis using the mixed linear model showed that the concentrations of both ALPPL2+ and THBS2+ EVs significantly correlate with changes in tumor size (based on RECIST measurements) in the longitudinal samples of CA19-9 non-secretors or secretors. In CA19-9 non-secretors the correlation p values are 0.003 and 0.006 for ALPPL2+ and THBS2+ EVs, respectively, whereas in CA19-9 secretors, the p values are 0.014 and 0.016 for ALPPL2+ and THBS2+ EVs, respectively. Our data indicates that EV based ALPPL2 and THBS2 could potentially serve as biomarkers for disease monitoring in patients with PDAC. (This work was supported in part by the Dorrance Family Fund and the Flinn Foundation) Citation Format: Kuntal Halder, Gayle Jameson, Erkut Borazanci, Wei Lin, Dereck Cridebring, Daniel Von Hoff, Haiyong Han. Extracellular vesicle based ALPPL2 and THBS2 as biomarkers for disease monitoring in patients with pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2497.

Evaluating Treatment Response in GEJ Adenocarcinoma: The Role of Pretherapeutic and Posttherapeutic Iodine Mapping.

Neoadjuvant therapy regimens have significantly improved the prognosis of GEJ (gastroesophageal junction) cancer; however, there are a significant percentage of patients who benefit from earlier resection or adapted therapy regimens, and the true response rate can only be determined histopathologically. Methods that allow preoperative assessment of response are lacking. The purpose of this retrospective study is to assess the potential of pretherapeutic and posttherapeutic spectral CT iodine density (IoD) in predicting histopathological response to neoadjuvant chemotherapy in patients diagnosed with adenocarcinoma of the GEJ. In this retrospective cohort study, a total of 62 patients with GEJ carcinoma were studied. Patients received a multiphasic CT scan at diagnosis and preoperatively. Iodine-density maps were generated based on spectral CT data. All tumors were histopathologically analyzed, and the tumor regression grade (TRG) according to Becker et al ( Cancer . 2003;98:1521-1530) was determined. Two experienced radiologists blindly placed 5 defined ROIs in the tumor region of highest density, and the maximum value was used for further analysis. Iodine density was normalized to the aortic iodine uptake. In addition, tumor response was assessed according to standard RECIST measurement. After assessing interrater reliability, the correlation of IoD values with treatment response and with histopathologic TRG was evaluated. The normalized ΔIoD (IoD at diagnosis - IoD after neoadjuvant treatment) and the normalized IoD after neoadjuvant treatment correlated significantly with the TRG. For the detection of responders and nonresponders, the receiver operating characteristic (ROC) curve for normalized ΔIoD yielded the highest area under the curve of 0.95 and achieved a sensitivity and specificity of 92.3% and 92.1%, respectively. Iodine density after neoadjuvant treatment achieved an area under the curve of 0.88 and a sensitivity and specificity of 86.8% and 84.6%, respectively (cutoff, 0.266). Iodine density at diagnosis and RECIST did not provide information to distinguish responders from nonresponders. Using the cutoff value for IoD after neoadjuvant treatment, a reliable classification of responders and nonresponders was achieved for both readers in a test set of 11 patients. Intraclass correlation coefficient revealed excellent interrater reliability (intraclass correlation coefficient, >0.9). Lastly, using the cutoff value for normalized ΔIoD as a definition for treatment response, a significantly longer survival of responders was shown. Changes in IoD after neoadjuvant treatment of GEJ cancer may be a potential surrogate for therapy response.

RECIST 1.1 Target Lesion Categorical Response in Metastatic Renal Cell Carcinoma: A Comparison of Conventional versus Volumetric Assessment.

Purpose To investigate Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) approximations of target lesion tumor burden by comparing categorical treatment response according to conventional RECIST versus actual tumor volume measurements of RECIST target lesions. Materials and Methods This is a retrospective cohort study of individuals with metastatic renal cell carcinoma enrolled in a clinical trial (from 2003 to 2017) and includes individuals who underwent baseline and at least one follow-up chest, abdominal, and pelvic CT study and with at least one target lesion. Target lesion volume was assessed by (a) Vmodel, a spherical model of conventional RECIST 1.1, which was extrapolated from RECIST diameter, and (b) Vactual, manually contoured volume. Volumetric responses were determined by the sum of target lesion volumes (Vmodel-sum TL and Vactual-sum TL, respectively). Categorical volumetric thresholds were extrapolated from RECIST. McNemar tests were used to compare categorical volume responses. Results Target lesions were assessed at baseline (638 participants), week 9 (593 participants), and week 17 (508 participants). Vmodel-sum TL classified more participants as having progressive disease (PD), compared with Vactual-sum TL at week 9 (52 vs 31 participants) and week 17 (57 vs 39 participants), with significant overall response discordance (P < .001). At week 9, 25 (48%) of 52 participants labeled with PD by Vmodel-sum TL were classified as having stable disease by Vactual-sum TL. Conclusion A model of RECIST 1.1 based on a single diameter measurement more frequently classified PD compared with response assessment by actual measured tumor volume. Keywords: Urinary, Kidney, Metastases, Oncology, Tumor Response, Volume Analysis, Outcomes Analysis ClinicalTrials.gov registration no. NCT01865747 © RSNA, 2023 Supplemental material is available for this article.

A pilot trial of autologous tumor infiltrating lymphocytes (lifileucel, LN-144) for patients with asymptomatic melanoma brain metastases.

TPS9606 Background: Melanoma brain metastases (MBM) are a leading cause of morbidity and mortality for patients with advanced melanoma. Modern systemic therapies are insufficient at controlling MBM, and median overall survival (OS) for pts with MBM is &lt; 1 year. Adoptive T cell therapy using tumor infiltrating lymphocytes (TIL) has demonstrated efficacy in advanced melanoma. Lifileucel (LN-144), an autologous TIL product, was recently shown to be safe and effective for patient with PD-1 refractory melanoma. Patients with active MBM were excluded from lifileucel trials to date. Methods: This single-center pilot trial (NCT05640193) is enrolling up to 10 pts with asymptomatic MBM from non-uveal melanoma to receive lifileucel. Patients must have ≥1 intracranial lesion measuring 5-30mm visible on MRI to be used as a target lesion for modified (m)RECIST measurement, progression on prior anti-PD-1 therapy (with or without anti-CTLA-4), progression on targeted therapy if BRAF V600E/K-mutated), ECOG PS ≤1, ≥1 resectable lesion(s) (≥1.5 cm), recovered from prior surgery/anticancer treatment-related AEs (grade ≤1). Patients are not eligible if they have symptomatic MBM and/or require corticosteroids of ≥10 mg/day of prednisone or equivalent. Lifileucel is generated from resected tumor in a centralized GMP process. The regimen includes nonmyeloablative lymphodepletion, lifileucel infusion, and a short course of high-dose IL-2. The primary endpoint is feasibility, defined as ≥7/10 patients who undergo tumor harvest receiving lifileucel infusion. Secondary endpoints are safety, feasibility of manufacturing lifileucel in patients with MBM, and brain metastasis response rate (BMRR) per mRECIST 1.1. Exploratory endpoints include overall objective response rate by mRECIST 1.1, best extracranial response rate, intracranial progression-free survival (PFS), overall PFS, OS. Extensive correlative analyses of peripheral blood mononuclear cells, plasma, tumors, and cerebrospinal fluid are planned to better understand MBM growth, treatment resistance, and response of the central nervous system to lifileucel. Clinical trial information: NCT05640193 .

Safety and efficacy of PIPAC in patients with ovarian cancer with peritoneal metastases: A first-in-US phase I study.

5554 Background: Epithelial ovarian cancer (EOC) is characterized by chemoresistant recurrences primarily confined to the intraperitoneal cavity, frequently leading to malignant small bowel obstructions. Intraperitoneal (IP) chemotherapy has been incorporated in EOC, but only in the first-line setting. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a novel IP drug delivery method that optimizes tissue penetration depth and drug distribution, to treat recurrent peritoneal malignancies. Recent trials outside the U.S. demonstrated partial to stable response following PIPAC in recurrent EOC. To date, no clinical trials have been completed investigating the role of PIPAC in EOC in the United States. Methods: We performed a multicenter prospective phase I trial using IP cisplatin 10.5 mg/m2 and doxorubicin 2.1 mg/m2 via PIPAC at 6-week intervals. Patients were eligible if they had recurrent disease with peritoneal metastasis; extraperitoneal metastasis was allowed. The primary endpoint was dose-limiting toxicity (DLT). Secondary endpoints included progression free survival, PCI scoring, RECIST measurements, and quality of life (QoL). The patients with gastric and uterine cancers’ toxicity data were used but given inherent prognostic differences the treatment efficacy for these patients were not used in this analysis. Adverse event (AE) monitoring was graded using CTCAE spanning 18 weeks. Following completion of treatment (³2 PIPACs) patients were followed up every 12 weeks. QoL was measured using patient-reported assessments at 0, 6, 12, and 18 weeks. Baseline demographics were summarized. Mean change in PCI was calculated between cycle (C) 1 and 2, and cycle 2 and 3. Toxicities attributed to the surgery or PIPAC were reported with highest grade for each patient. Results: Nine heavily pretreated, recurrent patients were enrolled in the trial: 7 with platinum-resistant recurrent EOC, 1 with uterine cancer, and 1 with gastric cancer. PIPAC completion rate was 71.4%. Median age of participants was 65 years. Median prior lines of chemotherapy were 4 (range 2 - 10). No surgical complications occurred in the cohort. Two patients came off study: one for G3 abdominal pain and the other for G3 anorexia. For the EOC cohort, the median PCI reduction was -1.4% (C1 to C2) and -2.8% (C1 to C3). One low-grade serous EOC patient demonstrated a partial response based on RECIST criteria and received 6 cycles. Two EOC patients showed an initial response based on PCI reduction, but progressed following Cycle 2. Overall, QoL was stable. Conclusions: PIPAC with cisplatin/doxorubicin in platinum-resistant ovarian cancer is well tolerated. Intraperitoneal responses were seen in a subset of low-grade serous ovarian cancer patients, which may warrant further study. Heavily pretreated, platinum-resistant high-grade EOC patients derived limited intraperitoneal control from PIPAC monotherapy. Clinical trial information: NCT04329494 .

Assessment of Tumor Burden and Response by RECIST vs. Volume Change in HPV+ Oropharyngeal Cancer – An Exploratory Analysis of Prospective Trials

<h3>Purpose/Objective(s)</h3> Tumor burden and response to therapy are commonly assessed using RECIST, however, unidimensional evaluation may not fully characterize disease dynamics. Using HPV+ oropharyngeal carcinoma as a tumor model, here we report a comparison of RECIST and volumetric measurements from 2 consecutive prospective trials of response-adaptive de-escalation of therapy. <h3>Materials/Methods</h3> Patients enrolled on 2 prospective phase II response adapted de-escalation trials for low- and high-risk HPV+ oropharynx cancer were included in the analysis. Patients received induction chemotherapy in trial 1 and induction chemoimmunotherapy in trial 2. Target lesions were initially assessed using RECIST 1.1 at baseline and post-induction therapy; patients with ≥ 50% response by RECIST received de-escalated radiation dose and treatment volume per protocol. Primary tumors and nodes were retrospectively delineated on diagnostic scans before and after induction therapy to ascertain volumetric tumor burden and response. Mean differences in RECIST and volume were evaluated with paired t-tests. Linear regression and chi-squared analysis were used to evaluate the correlation between percent change in tumor burden as well as de-escalation-concordance. Outcomes were overall excellent with use of 50% response by RECIST to guide de-escalation as reported previously. Analysis was thus done to identify proportion that responded 50% by volume. <h3>Results</h3> 104 patients (N=54 Trial 1, N=50 Trial 2) were evaluable. The mean post-induction therapy reduction in RECIST and volumetry was 3.13 cm and 25.18 cm³ respectively (<i>p</i><0.001). Primary tumor response to induction was greater than nodal response for both RECIST and volumetry. The mean percent difference in size post induction was 27.3% and 14.8% for RECIST and volumetry. Percent change in RECIST was correlated with volume change, <i>r</i> = 0.687 (<i>p</i><0.001). An increased proportion (<i>p</i>=0.008) of patients would be eligible for de-escalation based on response assessment (72% de-escalated by RECIST vs 89% by volumetry), and 4% (N=4) of patients who were de-escalated by RECIST would not meet criteria for de-escalation by volumetry. 2 of these 4 patients developed a local failure. <h3>Conclusion</h3> Here we report on volumetry as a novel response assessment tool. While volumetry was correlated with RECIST, a large proportion of variance in volume-based measurements was not accounted for by RECIST. Furthermore, volumetry-based assessment of tumor burden and response provided a more robust assessment of tumor response and subsequent decision to de-escalate therapy. Patients that responded by RECIST but not volume had higher rates of local failure. In addition, a higher proportion of patients met response criteria by volume and could have been considered for de-escalation.

Long-term Local Control and Overall Survival After Radiotherapy in Oligoprogressive Patients During Treatment With Checkpoint Inhibitors.

Recent studies described the safety and clinical utility of combined anti-programmed cell death protein-1 (anti-PD1) checkpoint inhibition with radiotherapy. However, long-term follow-up data are lacking. Abscopal effects have been hypothesized, though clinical proof is still scarce. We analyzed the efficacy and toxicity of combined (stereotactic) radiotherapy and anti-PD1 in consecutive oligoprogressive melanoma and non-small cell lung cancer (NSCLC) patients who were irradiated for 1 to 3 progressive metastases during anti-PD-1 in our institute between January 2017 and January 2019 and verified one-dimensional RECIST measurements by volumetric assessments. Out of 361 patients, 11 melanoma and 5 NSCLC patients were included in this series. Radiotherapy was applied after a median of 11 months (range=1-30 months) from the start of anti-PD1 treatment. No increased risk of adverse events for the combined treatments was observed. With a median follow-up of 4.9 years since the start of anti-PD1, 69% of patients were alive. Six of 16 patients had stable disease after a median follow-up of 4.1 years after radiotherapy. Abscopal effects were suspected in three out of 16 patients. However, if volumetric assessment was used, two of these patients already had tumor shrinkage prior to radiotherapy, not detected by one-dimensional measurements. Stereotactic radiotherapy for oligoprogressive disease during PD1-inhibition can induce long-term disease control. Although abscopal effects were suspected in three patients, they were not confirmed with volumetric assessment in two patients. The discrepancy found between one-dimensional and volumetric response assessment argues for including volumetric assessment in further studies.

Abstract 998: Mechanism of action of RXC004, a Wnt pathway inhibitor, in genetically-defined models of cancer

Abstract Background: RXC004 is a porcupine inhibitor, and thus a potent and selective inhibitor of Wnt ligand-dependent signalling. RXC004 is currently being investigated in a safety and tolerability study in cancer patients with solid tumours (NCT03447470). Certain Wnt pathway alterations, including loss-of-function RNF43 mutations and RSPO gene fusions, result in higher levels of the Wnt receptor Fzd on the cell surface increasing Wnt-ligand dependent signalling. These alterations are implicated in colorectal and pancreatic cancer. We present pre-clinical data on the effects of RXC004 in genetically defined models of cancer. Methods: RXC004 in vitro effects on the metabolic activity of both sensitive (genetically selected RNF43 mutant or RSPO fusion models) and insensitive (beta-catenin mutant model) colorectal and pancreatic tumour cells lines were assessed. To test if these effects translated in vivo, RXC004 was also evaluated in an in vivo FDG-PET study in an RSPO fusion tumour cell line. In addition, as we had previously noted that RXC004 caused cell differentiation in an RSPO fusion model, we studied if pre-treatment with RXC004 would affect subsequent tumour growth post RXC004 induced cell differentiation in vivo. Results: In tumour cell lines in vitro, RXC004 significantly reduced glucose uptake only in genetically selected tumour cell lines. In vivo FDG-PET studies also showed a reduction in FDG-PET signals post 7 days treatment of 5mg/kg QD RXC004. Imaging demonstrated that MaxSUV (maximum standardised uptake value) decreased by 31% in RXC004 treated versus vehicle treated tumours, furthermore biodistribution of PET ligand was significantly inhibited in tumours post 7 days RXC004 treatment. Pre-treatment of RXC004 in an in vivo mouse xenograft model for 7 days resulted in a significant reduction in tumour growth when tumour fragments from these pre-treated mice were re-implanted into naïve mice (P&amp;lt;0.05). Conclusion: These data demonstrate that RXC004 monotherapy results in tumour cell differentiation accompanied by reduced metabolic activity in genetically selected tumours. RXC004-induced cell differentiation may therefore continue to provide patient benefit even post dosing. Moreover, FDG-PET imaging in clinical studies may allow early detection of the positive effects of RXC004 in a non-invasive manner, and prior to any changes in tumour volume by conventional RECIST measurements. Citation Format: Caroline Phillips, Simon Woodcock, Catherine Eagle, Andrew Saunders, Craig Tilston, Inder Bhamra, Richard Armer. Mechanism of action of RXC004, a Wnt pathway inhibitor, in genetically-defined models of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 998.

Phase II trial of opaganib in patients with metastatic castration-resistant prostate cancer progressing on abiraterone or enzalutamide (NCT04207255).

TPS191 Background: Opaganib (Yeliva, ABC294640) is a first-in-class, sphingosine kinase-2 (SK2) selective inhibitor, with anticancer, anti-inflammatory and anti-viral activities. SK2, a lipid kinase catalyzes formation of the lipid signaling molecule sphingosine 1-phosphate (S1P). S1P promotes cancer growth, and proliferation and pathological inflammation, including inflammatory cytokine production. Specifically, by inhibiting the SK2 enzyme, opaganib blocks the synthesis of S1P which regulates fundamental biological processes such as cell proliferation, migration, immune cell trafficking and angiogenesis, and are also involved in immune-modulation and suppression of innate immune responses from T cells. Opaganib is a sphingosine-competitive inhibitor of SK2 and also inhibits dihydroceramide desaturase. Opaganib has antitumor activity against human and murine prostate cancer cell lines, and in xenograft (LNCaP) and syngeneic (MycCAP, TRAMP-C1) murine tumor models. In addition to its target effect of reducing sphingosine-1-phosphate, opaganib reduces both MYC and AR proteins through its kinase-blocking and desaturase-inhibiting properties, respectively. Methods: The study is open to patients with mCRPC who have been treated with at least one newer androgen antagonist (abiraterone or enzalutamide) and no prior chemotherapy for castration-resistant disease. Patients who are failing either abiraterone or enzalutamide may enroll, with the addition of opaganib. The trial design includes brief safety lead-in cohort 1a (abiraterone + opaganib 250 mg Q 12hr, 3/3 enrolled) and 1b (enzalutamide + opaganib 250 mg Q 12hr, 3/3 enrolled). These cohorts have been completed without any DLTs. We are now enrolling cohort 2 (abiraterone + opaganib 500 mg Q 12hr, 0/27 enrolled) and cohort 3 (enzalutamide + opaganib 500 mg Q 12hr, 8/27 enrolled). A total of 60 patients will be enrolled and response will be evaluated after 4 cycles (28 days/cycle) using a composite metric based on PSA, bone scan and RECIST measurements per PCWG3 criteria. Safety and tolerability will be monitored, and dose modifications will be allowed. Primary endpoint is disease control (stable disease or better) after 4 cycles. Secondary endpoints include overall survival, radiographic progression-free survival and PSA progression-free survival. Correlative studies include assessment of quality of life (QOL), circulating MDSCs, immune cells and clones with amplified AR or MYC. Supported by NIH grant P01 CA203628. Clinical trial information: NCT04207255.

Desmoplastic mesenteric lesions do not respond radiographically to peptide receptor radionuclide therapy.

177 Lu-Dotatate treatment is indicated for progressive, well-differentiated, small bowel neuroendocrine tumours) NETs. These tumours often metastasise to mesenteric lymph nodes and produce a desmoplastic reaction, consisting of tumour cells interspersed with fibrotic tissue. We hypothesised that, in patients treated with 177 Lu-Dotatate, mesenteric tumours would remain stable even as liver tumour size changes were observed. We retrospectively reviewed the records of all patients treated with 177 Lu-Dotatate between April 2018 and December 2019. Among patients with desmoplastic mesenteric tumours and liver metastases, we evaluated changes in tumour size of mesenteric and liver lesions based on pre- and post-treatment anatomic scans. As a result of the infrequency of objective radiographic response, any reported changes in tumour size were considered significant. Twenty-one patients met the inclusion criteria: nine had evidence of shrinkage of liver lesion(s), one had mild progression of liver lesions, seven had stable hepatic disease and four had a mixed hepatic response. Two of the patients with hepatic tumour shrinkage met the criteria for a partial response via RECIST 1.1 (https://recist.eortc.org). Desmoplastic mesenteric lesions remained unchanged in size, regardless of the changes detected in liver lesions. In conclusion, 177 Lu-Dotatate does not impact desmoplastic mesenteric tumours which are typically associated with midgut NETs. Patients whose disease is predominantly confined to desmoplastic mesenteric lesions are unlikely to respond radiographically to peptide receptor radionuclide therapy. Moreover, the inclusion of desmoplastic mesenteric lesions as target lesions in RECIST measurements tends to increase rates of disease stability vs response or progression.

Radiographic response of desmoplastic mesenteric lesions to peptide receptor radionuclide therapy (PRRT).

362 Background: 177Lu-dotatate PRRT is indicated in well-differentiated, SSTR+ small bowel NETs. These tumors often metastasize to mesenteric lymph nodes and produce a desmoplastic reaction, consisting of tumor cells mixed with fibrotic tissue. We hypothesized that in patients treated with 177Lu-dotatate, mesenteric tumors would remain stable even as liver tumor size changes were observed. Methods: We retrospectively reviewed the records of all patients treated with 177Lu-dotatate between 4/2018 and 12/2019. Among patients with desmoplastic mesenteric tumors and liver metastases, we evaluated changes in tumor size of mesenteric and liver lesions based on pre and post-treatment radiology reports. Due to the infrequency of objective radiographic response (ORR), any reported changes in tumor size were considered significant. Scans were subsequently reviewed by a radiologist to confirm findings. Results: 21 patients met the inclusion criteria: 9 had evidence of shrinkage of liver lesion(s), 1 report described mild progression of liver lesions, 7 described stable hepatic disease and 4 described mixed hepatic progression/response. 2 of the patients with hepatic tumor shrinkage met criteria for PR by RECIST 1.1. Desmoplastic mesenteric lesions remained unchanged in size, regardless of the changes detected on liver lesions. Conclusions: 177Lu-dotatate does not impact desmoplastic mesenteric tumors typically associated with midgut NETs. Patients whose disease is confined to desmoplastic mesenteric lesions are unlikely to respond radiographically to PRRT. Moreover, the inclusion of desmoplastic mesenteric lesions as target lesions in RECIST measurements increases rates of disease stability versus response or progression.

Serum soluble mesothelin-related protein (SMRP) and fibulin-3 levels correlate with baseline malignant pleural mesothelioma (MPM) tumor volumes but are not useful as biomarkers of response in an immunotherapy trial

ObjectivesSoluble mesothelin-related protein (SMRP) and fibulin-3 serum levels may serve as diagnostic and prognostic biomarkers of malignant pleural mesothelioma (MPM). Here, we evaluate these markers for correlation to tumor volume, prognosis and response assessment in a clinical trial of immunogene therapy in combination with chemotherapy. Materials and methodsSerial serum levels of SMRP and fibulin-3 were measured in adult patients with biopsy-proven MPM enrolled in two prospective clinical trials. Pre-therapy computed tomography (CT) measurements of tumor burden were calculated and correlated with pre-therapy serum SMRP and fibulin-3 levels in these two trials. Serological data were also correlated with radiological assessment of response using Modified RECIST criteria over the first 6 months of intrapleural delivery of adenovirus-IFN alpha (Ad.IFN-α) combined with chemotherapy. ResultsA cohort of 58 patients who enrolled in either a photodynamic therapy trial or immunotherapy clinical trial had available imaging and SMRP serological data for analysis of whom 45 patients had serological fibulin-3 data. The cohort mean total tumor volume was 387 cm3 (STD 561 cm3). Serum SMRP was detectable in 57 of 58 patients (mean 3.8 nM, STD 6.0). Serum fibulin-3 was detected in 44 of 45 patients (mean 23 ng/mL, STD 14). At pre-therapy baseline in these two trials, there was a strong correlation between tumor volume and serum SMRP levels (r = 0.61, p < 0.001), and a moderate correlation between tumor volume and serum fibulin-3 levels (r = 0.36, p = 0.014). Twenty-eight patients in the immunotherapy trial had longitudinal serologic and radiographic data. Fold-changes in SMRP and fibulin-3 did not show significant correlations with modified RECIST measurements. ConclusionsAlthough our data show correlations of SMRP and fibulin-3 with initial tumor volumes as measured by CT scanning, the use of SMRP and fibulin-3 as serological biomarkers in the immunotherapy trial were not useful in following tumor response longitudinally.

CT-based whole-body tumor volumetry versus RECIST 1.1: Feasibility and implications for inter-reader variability

PurposeTo investigate whether volumetric measurements of the whole-body tumor volume (WBTV) are feasible and whether they improve inter-reader variability in patients in whom conventional RECIST 1.1 assessment yielded discordant results. Methods50 patients (29 male, 21 female, mean age 60.9 ± 12.3 years) with metastases of solid tumors in whom three readers had selected different sets of target lesions and subsequently reached different results for response assessment (progressive vs. non-progressive disease) when using RECIST 1.1 were included. In a second read, all readers performed volumetric measurements of the WBTV on neck/chest/abdomen/pelvis CTs and measured the time needed for these measurements. Cohen’s kappa and Fleiss kappa statistics were used to compare the intra- and inter-reader agreement for response assessment. ResultsIn 8/50 patients (16 %), the WBTV was too extensive for volumetric measurements and these patients were therefore excluded. In the remaining 42 patients, WBTV measurements required a mean time of 18 min and 9 s. Readers assigned the same response categorizations based on unidimensional RECIST measurements and WBTV measurements in 15/42 patients (33 %), 24/42 patients (57 %) and 30/42 patients (71 %) for reader 1,2 and 3 respectively. When performing response assessment based on WBTV measurements, the three readers agreed in 40/42 patients (95 %) regarding the distinction progressive vs. non-progressive disease, resulting in a near-perfect agreement on a patient-based level (Fleiss’ κ = 0.921, 0.95-CI:0.746–1.095). ConclusionsWBTV measurements yielded an almost perfect inter-reader agreement in a cohort of patients, in which three readers reached discordant response assessment results when following conventional RECIST 1.1 guidelines. This supports the hypothesis, that a limited subset of metastases may not be sufficient to accurately assess response-to-treatment.

Novel, non-invasive imaging approach to identify patients with advanced non-small cell lung cancer at risk of hyperprogressive disease with immune checkpoint blockade

PurposeHyperprogression is an atypical response pattern to immune checkpoint inhibition that has been described within non-small cell lung cancer (NSCLC). The paradoxical acceleration of tumor growth after immunotherapy has been...

Clinical characteristics and anti-PD-(L)1 treatment outcomes of KRAS-G12C mutant lung cancer compared to other molecular subtypes of KRAS-mutant lung cancer.

9596 Background: KRAS mutations are identified in approximately 30% of NSCLC. There are no FDA approved targeted therapies for patients with KRAS-mutant non-small cell lung cancer (NSCLC) but novel direct inhibitors of KRAS G12C have shown some activity in early phase clinical trials. We hypothesized that patients with KRAS-G12C mutations may have distinct clinical characteristics and responses to systemic therapies compared to patients with non-G12C subtypes. Methods: We identified patients with KRAS-mutant lung cancers who underwent next-generation sequencing with MSK-IMPACT, between January 2014 and December 2018. Baseline characteristics were compared with the Chi-square and Fisher’s exact test for categorical data and Wilcoxon rank-rum test for continuous data. Overall survival was calculated from time of diagnosis of metastatic/recurrent disease to date of death or last follow up, with left truncation to account for time of MSK-IMPACT. Overall survival was compared between groups using the Cox proportional-hazards model. Response evaluations where performed by independent thoracic radiologists according to RECIST 1. and compared between group with the Fisher’s exact test. Results: We identified 1194 patients with KRAS -mutant NSCLC, 772 with recurrent or metastatic disease. Of patients with advanced disease, 46% (352/772) had mutations in KRAS-G12C and 54% harbored non-G12C mutations (15% G12D, 16% G12V, 8% G12A, 4% G13D). Co-mutation patterns were similar with respect to KEAP1 (p=0.9) and STK11 (p=1.0). Patients with non-G12C mutations had a higher proportion of never smokers (10% vs 1.4% p&lt;0.001). The median OS from diagnosis was 13 months for G12C and non-G12C patients (p=0.99). 45% (347/772) received 1L or 2L line treatment with PD-(L)1 inhibitor. RECIST measurements were available for 290/347 cases (84%). ORR with anti-PD-(L)1 treatment was 24% vs 28% in G12C vs non-G12C patients (p=0.5). In patients with PD-L1 50% (n=103), ORR was 39% for G12C vs 58% non-G12C patients (p=0.06). Conclusions: KRAS G12C mutations are present in 12% of patients with NSCLC and represent a relevant subtype of NSCLC given KRAS G12C inhibitors now in clinical development. Baseline characteristics including co-mutation patterns are similar between patients with G12C and non-G12C, except for smoking history. The efficacy of KRAS G12C direct inhibitors will need to be compared to other available therapies for KRAS mutant NSCLC (chemotherapy and PD-(L)1 inhibitors) to identify most effective therapeutic strategy.

A phase II trial of pharmacological ascorbate, gemcitabine, and nabpaclitaxel for metastatic pancreatic cancer.

TPS791 Background: FOLFIRINOX or gemcitabine/nab-paclitaxel are both frontline chemotherapy options for patients with metastatic pancreas cancer. For most who cannot tolerate the triplet, the latter doublet is the preferred option. Through previous work by our group, pharmacologic ascorbate is known to synergize with gemcitabine; preliminary in vitro data from our group suggests a similar synergistic response with paclitaxel. Though ascorbate has been utilized in cancer therapy, few robust trials have investigated intravenous delivery of ascorbate to deliver plasma concentrations that are cytotoxic to tumor cells. Our prior studies have demonstrated ascorbate induces oxidative stress and cytotoxicity in pancreatic cancer cells; this cytotoxicity appears to be greater in tumor vs. normal cells. We hypothesize that production of hydrogen peroxide mediates the increased susceptibility of pancreatic cancer cells to ascorbate-induced metabolic oxidative stress, resulting in improved treatment outcomes, which has led to the development of the clinical trial (NCT02905578). Methods: All participants receive gemcitabine (1000 mg/m2 weekly) and nab-paclitaxel (125 mg/m2) on cycle days 1, 8, and 15 of a 28-day cycle. Participants are randomized to ± pharmacologic ascorbate (75-gram infusion 3x weekly) in addition to chemotherapy. Study therapy continues until tumor progression. The primary objective is to determine overall survival in patients when treated with combination gemcitabine, nab-Paclitaxel and high-dose ascorbic acid compared to gemcitabine and nab-paclitaxel in patients with non-resectable pancreatic cancer. Secondary objectives include determining objective response rate as well as progression free survival using RECIST 1.1 criteria employing a blinded reviewer for RECIST measurements. The study opened to accrual in 2018 with a goal of enrolling 65 participants. Oversight.Study is conducted under IND 105715 (J. Cullen, sponsor). The University of Iowa Biomedical IRB (IRB-01) serves as the IRB of record. Clinical trial information: NCT02905578.

Analysis of AKR1B10 levels among various groups of breast cancer patients.

e14548 Background: Aldo-keto reductase 1B10 (AKR1B10) is a protein that is primarily expressed in human colon and small intestine, but induced in hepatocellular carcinoma and non-small cell lung cancer. Our recent studies have revealed that AKR1B10 is overexpressed in primary, metastatic, and recurrent cancers of the breast. Methods: We recruited four cohorts of patients: Patients with breast cancer undergoing primary surgery from whom we procured breast cancer and matched normal adjacent tissue to evaluate AKR1B10 expression in primary tumors. The matched serum samples were collected before surgery and at various time points after the surgery (approximately 3 days, 7 days, and 1 month Patients with recurrent or advanced (metastatic) breast cancer. Serum samples were collected and serially monitored for up to 2years before and during metastatic therapy and correlated with RECIST measurements. Patients with locally advanced disease undergoing neoadjuvant chemotherapy. AKR1B10 serum levels were monitored during therapy and correlated with RECIST measurements. Healthy individuals with normal mammograms were recruited and submitted serum samples for AKR1B10 serum measurements. Results: AKR1B10 rapidly cleared the serum of early stage breast cancer patients with an estimated half-life of 24-30 hours. Serum AKR1B10 levels correlated strongly with tissue IHC staining and PR positivity but not with RECIST levels or Oncotype Dx scores. Neoadjuvant chemotherapy did not affect serum AKR1B10 levels. Individuals with normal mammograms displayed substantially lower levels of AKR1B10 than breast cancer patients. Patients with DCIS also displayed elevated serum AKR1B10 levels. Conclusions: AKR10 may serve as tumor marker to independently identify high risk patients whose tumors have intermediated risk Oncotype Dx scores and may also identify early breast cancers in patients with equivocal breast biopsies.